The discovery of suitable ultrasound contrast imaging agents for human diagnostic applications has been the focus of considerable research and development in recent years. This research has yielded several potential ultrasound contrast imaging agents such as gas-filled microbubbles encapsulated with denatured albumin as described in U.S. Pat. Nos. 4,572,203, 4,718,433, 4,774,958, and 4,844,882 which have issued to Feinstein and Molecular Biosystems, Inc.; gas-filled microbubbles encapsulated by liposomes as described in U.S. Pat. Nos. 5,088,499 and 5,123,414 which have issued to Unger; gas-filled, free microbubbles as described in U.S. Pat. Nos. 5,393,524, and 5,409,688 which have issued to Sonus Pharmaceuticals, Inc.; and saccharide containing solid particles that are mixed with a diluent to produce an ultrasound contrast agent as described in U.S. Pat. Nos. 4,442,843 and 4,681,119, both assigned to Schering AG.
Even though each of these compositions is unique in its basic physical characteristics, each is provided in the form of an aqueous medium or suspension that is to be administered by intravenous infusion to the patient. This is a significant disadvantage to the clinical use of these agents because it introduces additional variables, such as injection rate and volume to be administered, that could adversely impact the efficacy of the agent. In some instances, large volumes of the contrast agent may be required which is undesirable from a patient comfort perspective and is preferably avoided. Moreover, one of the inherent advantages of the use of ultrasound as the imaging modality is the non-invasive nature of the application. When a contrast imaging agent is administered intravenously, the non-invasive advantage presented by this modality is diminished and a decision must be made as to whether the diagnostic procedure warrants the added cost and delays associated with intravenous infusion. This is particularly important when an ultrasound is to be conducted in connection with a cardiac stress test.
An inhalable gaseous ultrasound imaging agent was described in PCT International publication number WO 93/06869 that comprised a gas or mixture of gases that were capable of forming bubbles after administration to a patient. As disclosed therein, the gaseous compositions that were believed to be suitable were those that were poorly soluble in oil, but somewhat more soluble in water. More specifically, WO 93/06869 disclosed that those gases with very low oil:gas partition coefficients, less than about 0.1 would be less effective than those with higher oil:gas partition coefficients and stated that preferred suitable compounds would be compounds described as weak or poor anesthetic agents, e.g., nitrous oxide, xenon, ethylene, sulfur hexafluoride and argon. Unfortunately, none of the compounds described in WO 93/06869 have ultimately been shown to have any utility as ultrasound contrast agents as they have failed to form bubbles in vivo. The search for an inhalable contrast imaging agent continues, however, because of the considerable potential associated with the use of an inhalable gas as an ultrasound contrast imaging agent. An inhalable agent would not require intravenous infusion, would be easily administered and not require large dosage volumes, and could readily be administered without concern for substantial added cost, delays or additional invasiveness.
Perfluorocarbons are currently used in biomedical applications including blood substitutes, imaging agents and liquid ventilation media. Many perfluorocarbon derivatives are used as anesthetic agents that are somewhat resistant to biotransformation. They are partially fluorinated and readily dissolve in blood on passage from the lung alveoli. This solubility factor significantly limits their use as ultrasound contrast agents. Perfluorocarbons are insoluble in blood and intravenous injection of the neat perfluorocarbon liquid is likely to cause liquid embolism and instant death.
A need exists, therefore, for a gaseous ultrasound contrast imaging agent that can be inhaled by a patient and that is capable of providing contrast after administration.